An investigation of CYP2D6 genotype and response to metoprolol CR/XL during dose titration in patients with heart failure: a MERIT-HF substudy.

To explore the pharmacogenetic effects of the cytochrome P450 (CYP)2D6 genotype in patients with systolic heart failure treated using controlled/extended-release (CR/XL) metoprolol, this study assessed the CYP2D6 locus for the nonfunctional *4 allele (1846G>A; rs3892097) in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF; n = 605). Participants were characterized as extensive, intermediate, or poor metabolizers (EMs, IMs, or PMs, respectively), based on the presence of the CYP2D6*4 allele (EM: *1*1, 60.4%; IM: *1*4, 35.8%; and PM: *4*4, 3.8%). Plasma metoprolol concentrations were 2.1-/4.6-fold greater in the IM/PM groups as compared with the EM group (P < 0.0001). Metoprolol induced significantly lower heart rates and diastolic blood pressures during early titration, indicating a CYP2D6*4 allele dose-response effect (P < 0.05). These effects were not observed at maximal dose, suggesting a saturable effect. Genotype did not adversely affect surrogate treatment efficacy. CYP2D6 genotype modulates metoprolol pharmacokinetics/pharmacodynamics during early titration; however, the MERIT-HF-defined titration schedule remains recommended for all patients, regardless of genotype.

The large-scale placebo-controlled beta-blocker studies in systolic heart failure revisited: results from CIBIS-II, COPERNICUS and SENIORS-SHF compared with stratified subsets from MERIT-HF.

AIMS: The four pivotal beta-blocker trials in heart failure (HF) had different inclusion criteria, making comparison difficult without patient stratifying. The aim of this study was to compare, in similar patients, the effects of bisoprolol, metoprolol controlled release/extended release (CR/XL), carvedilol and nebivolol on (i) total mortality, (ii) all-cause mortality or hospitalization due to cardiovascular causes (time to first event), (iii) all-cause mortality or hospitalization because of HF and (iv) tolerability, defined as discontinuation of randomized treatment. METHODS: We compared stratified (s ) subsets in MERIT-HF with patients in CIBIS-II [New York Heart Association (NYHA) class III/IV and ejection fraction (EF) ≤ 35%] and COPERNICUS (NYHA III/IV and EF <25%) and in patients with systolic HF in SENIORS-SHF (age ≥ 70 years and EF ≤ 35%). RESULTS: The annual mortality rates in the placebo and beta-blocker arms were: (i) CIBIS-II (n = 2647), 13.2% vs. 8.8% (relative risk reduction 34%, 95% CI: 19-46, P < 0.0001) and MERIT-HFs (n = 2002), 14.8% vs. 8.6% (relative risk reduction 42%, 95% CI: 24-56, P < 0.0001); (ii) COPERNICUS (n = 2289), 19.7% vs. 12.8% (relative risk reduction 35%, 95% CI: 19-48, P = 0.0014) and MERIT-HFs (n = 795), 19.1% vs. 11.7% (relative risk reduction 39%; 95% CI: 11-58, P = 0.0086); (iii) SENIORS-SHF (n = 1359), 11.3% vs. 9.7% (relative risk reduction 16%, NS) and MERIT-HFs (n = 985), 14.8% vs. 10.1% (relative risk reduction 32%, 95% CI: 2-53, P = 0.038). The effects on the other outcomes assessed were similar. Analyses indicated fewer discontinuations from randomized treatment on beta-blockers compared with placebo in COPERNICUS and the MERIT-HFs subsets. CONCLUSION: The efficacy and tolerability of bisoprolol, carvedilol and metoprolol CR/XL are similar in patients with systolic HF, irrespective of NYHA class or ejection fraction. Nebivolol is less effective and not better tolerated.

The association between neutrophil gelatinase-associated lipocalin and clinical outcome in chronic heart failure: results from CORONA*.

OBJECTIVE: To study the prognostic value of neutrophil gelatinase-associated lipocalin (NGAL) in chronic heart failure (HF) of ischaemic aetiology. BACKGROUND: Neutrophil gelatinase-associated lipocalin is a marker of kidney injury as well as matrix degradation and inflammation and has previously been shown to be increased in HF. We investigated whether serum NGAL levels could provide prognostic information in chronic HF. METHODS: We assessed NGAL as a predictor of primary outcomes (cardiovascular death, nonfatal stroke and nonfatal myocardial infarction, n = 307) and all-cause mortality (n = 321), cardiovascular mortality (n = 259) and hospitalization (n = 647) as well as the number of hospitalizations during follow-up for all (n = 1934) and CV causes (n = 1204) in 1415 patients with chronic HF (≥60 years, New York Heart Association class II-IV, ischaemic systolic HF) in the CORONA population, randomly assigned to 10 mg rosuvastatin or placebo. Results. Multivariate analysis revealed that NGAL added significant information when adjusting for clinical variables, but was no longer significant when further adjusting for apolipoprotein A-1 (ApoA-1), glomerular filtration rate (GFR), C-reactive protein (CRP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). However, belonging to the highest NGAL tertile was associated with more frequent hospitalization, even after adjusting for clinical variables, GFR and ApoA-1, but not after adjusting for CRP and NT-proBNP. There was no interaction between rosuvastatin treatment and NGAL. Conclusion. Neutrophil gelatinase-associated lipocalin added no significant information to NT-proBNP and GFR in a multivariate model for primary and secondary end-points.

High apoB/apoA-I ratio is associated with increased progression rate of carotid artery intima-media thickness in clinically healthy 58-year-old men: experiences from very long-term follow-up in the AIR study.

OBJECTIVES: The aim of the present study was to investigate the relationship between atherosclerotic progression rate as measured by carotid artery IMT during very long-term follow-up in clinically healthy men and a number of baseline risk factors of potential importance for atherosclerosis progression including apoA-I, apoB, apoB/apoA-I ratio, other lipid variables including LDL particle size, body composition variables, blood pressure, smoking, fasting blood glucose and insulin, and also hsCRP. BACKGROUND: Low-density lipoprotein (LDL) is associated with increased carotid IMT progression rate during long-term follow-up, whereas the relationship between newer biomarkers such as apoB/apoA-I ratio and carotid artery IMT progression rate has been less investigated. METHODS: 58-year-old men identified by screening in the community (n=391) with varying degrees of obesity and insulin sensitivity were examined with high-resolution B-mode ultrasound at baseline and after 3, and 8.9 years of follow-up (n=305 investigated after 8.9 years). The carotid arteries were examined bilaterally, and the mean intima-thickness was calculated for 10mm sections of the composite of common carotid arteries and bulbs (IMT(composite)). Serum levels of apoB and apoA-I were measured using a turbidimetric method. Uni- and multi-variable analyses were performed to study the relationship between carotid IMT(composite) progression rate and risk factors. RESULTS: In a multi-variable analysis including all baseline variables only the apoB/apoA-I ratio (p=0.003; beta=0.181, standard error=0.003) and serum insulin (p=0.026; beta=-0.133, standard error=0.000) was significantly related to IMT(composite) progression rate. CONCLUSION: The results indicate that apoB/apoA-I ratio is an important risk factor for predicting atherosclerotic progression rate during very long-term follow-up in clinically healthy middle-aged men.

Association between impaired glucose tolerance and carotid atherosclerosis: a study in 64-year-old women and a meta-analysis.

BACKGROUND AND AIMS: Impaired glucose tolerance (IGT) is regarded as a transient metabolic state leading to type-2 diabetes, and is known to predict future risk of cardiovascular disease. This study was designed to investigate if IGT is associated with subclinical atherosclerosis. METHODS AND RESULTS: In a population-based cohort of 64-year-old women, a group with IGT determined by repeated oral glucose tolerance tests (n=205) was compared with healthy women with normal glucose tolerance (NGT, n=188). Intima-media thickness (IMT) and plaques in the common carotid arteries (CCA) and bulbs were measured by ultrasound. The 95% confidence interval (CI) of the difference between the IGT and NGT groups was -0.03 to 0.03mm. There was no difference in carotid bulb IMT or in the occurrence, size, and characteristics of plaques between the IGT and NGT groups. A meta-analysis was used to calculate summary measures of 12 reviewed studies showing a difference of 0.030 (95% CI 0.012-0.048) mm in carotid IMT between IGT and NGT groups. Heterogeneity in IMT differences between studies was shown. CONCLUSIONS: In our population-based cohort of 64-year-old women, IGT was not associated with increased occurrence of subclinical atherosclerosis. However, a meta-analysis of 12 studies, including our current study, showed that IGT was associated with a small increase in the CCA IMT.

Circulating oxidized LDL is associated with the occurrence of echolucent plaques in the carotid artery in 61-year-old men.

OBJECTIVE: The aim of this study was to elucidate the relationship between the echogenicity of carotid artery plaques and the following risk factors: circulating oxLDL, hsCRP, the metabolic syndrome (MetS), and several of the traditional cardiovascular (CV) risk factors. MATERIAL AND METHODS: A cross-sectional population-based study of 513 sixty-one-year-old men. The levels of circulating oxLDL were determined in plasma samples by sandwich ELISA utilizing a specific murine monoclonal antibody (mAb-4E6). High-sensitivity CRP was measured in plasma by ELISA. Plaque occurrence, size and echogenicity were evaluated from B-mode ultrasound registrations in the carotid arteries. Plaque echogenicity was assessed based on a four-graded classification scale. RESULTS: A higher frequency of echolucent carotid plaques was observed with increasing levels of oxLDL and systolic blood pressure (p = 0.008 and p = 0.041, respectively). Subjects with the MetS had a significantly higher frequency of echogenic plaques than subjects without the MetS (p = 0.009). In a multiple logistic regression analysis, oxLDL turned out to be independently associated with echolucent carotid plaques. CONCLUSIONS: The occurrence of echolucent carotid plaques was associated with oxLDL and systolic blood pressure, and oxLDL was associated with echolucent carotid plaques independently of systolic blood pressure.

Are serum adiponectin concentrations in a population sample of 64-year-old Caucasian women with varying glucose tolerance associated with ultrasound-assessed atherosclerosis?

OBJECTIVE: To examine whether serum adiponectin concentrations were associated with subclinical atherosclerosis assessed as intima media thickness (IMT) in the carotid arteries in Caucasian women with varying degrees of glucose tolerance. RESEARCH DESIGN AND METHODS: From a population-based cohort of 64-year-old Swedish women, 533 subjects with type 2 diabetes (DM2, n=177), impaired glucose tolerance (IGT; n=178) or normal glucose tolerance (NGT, n=178) were recruited. Anthropometrics, usual cardiovascular risk factors were examined and ultrasound examination of the carotid arteries was performed. RESULTS: Women with low adiponectin concentrations were characterized by thick IMT, higher prevalence of DM2, history of previous myocardial infarction, angina pectoris, anti-hypertensive treatment and high body mass index (BMI), waist circumference, plasma insulin, serum triglycerides, fasting glucose, HbA1c, and low serum HDL cholesterol levels. Carotid IMT correlated with HbA1c (r=0.24, P<0.001), waist circumference (r=0.22, P<0.001), plasma insulin (r=0.19, P<0.001), BMI (r=0.18, P<0.001), DM2 (r=0.16, P<0.001), systolic blood pressure (r=0.16, P<0.001), blood glucose (r=0.16, P<0.001), triglycerides (r=0.15, P<0.001), and reversely to adiponectin (r=-0.11, P=0.01), HDL cholesterol (r=-0.13, P=0.004), and alcohol intake (r=-0.087, P<0.05). A more detailed analysis of underlying associations was difficult due to a high co-linearity between these variable. CONCLUSIONS: Low serum adiponectin concentrations were associated with increased carotid artery IMT, and several risk factors for cardiovascular diseases, mainly those constituting the metabolic syndrome.

apoB/apoA-I ratio is related to femoral artery plaques and is predictive for future cardiovascular events in healthy men.

OBJECTIVES: The aim of the present study was to investigate the association between serum concentrations of apoB, apoA-I and the apoB/apoA-I ratio and future cardiovascular events in a group of healthy 58-year-old men during 6.6 years of follow-up. A further aim was to investigate the concentrations of apoB, apoA-I and the apoB/apoA-I ratio to the association of plaque occurrence in the carotid and femoral arteries. BACKGROUND: Previous studies have shown that the apoB/apoA-I ratio is an important cardiovascular risk factor, whereas the association between apoB/apoA-I ratio and presence of atherosclerotic plaques in the carotid and femoral arteries has been less investigated. METHODS: The carotid and femoral arteries were examined by high-resolution B-mode ultrasound in 391, 58-year-old men identified by screening in the city of Göteborg, Sweden. Assessment of plaque occurrence and measurement of apolipoproteins (apoA-I and apoB) was performed. RESULTS: Subjects with an apoB/apoA-I ratio >/=0.9 had a significantly increased risk to suffer a cardiovascular event during 6.6 years of follow-up (OR 3.07, 95% CI 1.22-7.71), while no difference in risk for cardiovascular events was observed for subjects with LDL cholesterol >3.4 mmol/L compared to subjects <3.4 mmol/L (OR 1.04, 95% CI 0.37-2.46). A greater risk for plaques in the femoral artery was also observed in subjects with an apoB/apoA-I ratio >/=0.9 compared to subjects <0.9 (OR 3.06, 95% CI 1.22-7.70). In a multiple logistic regression model, both elevated apoB/apoA-I ratio and plaque occurrence in the femoral artery were of significant importance for cardiovascular events during follow-up. CONCLUSIONS: The results showed that the apoB/apoA-I ratio was associated with arteriosclerosis in the femoral artery, and predicted future cardiovascular events. These observations, and the fact that apoB and apoA-I can be measured in the non-fasting state with high precision, in combination with the finding that LDL cholesterol did not predict cardiovascular disease, support results from other studies that the apoB/apoA-I ratio may be a superior risk marker for cardiovascular disease.

Oxidized low-density lipoprotein in plasma is a prognostic marker of subclinical atherosclerosis development in clinically healthy men.

OBJECTIVE: To investigate the association between plasma oxidized low-density lipoprotein (OxLDL) and the progress of clinically silent atherosclerosis, as measured by ultrasound in the carotid arteries. DESIGN: Prospective, observational study with more than 3 years of follow-up. SETTING: One-centre study at university hospital. MATERIAL AND METHODS: The subjects (n = 326) were obtained by stratified sampling from a population sample of men who were 58 years old at baseline. Carotid artery intima-media thickness (IMT) was measured bilaterally by high-resolution B-mode ultrasound at baseline and after follow-up. Plasma OxLDL cholesterol concentrations and conventional cardiovascular risk factors were measured at study entry. Automated measurements of IMT were performed. Plaque occurrence and size were assessed (plaque status). Plasma OxLDL at entry was measured by a specific monoclonal antibody, mAb-4E6. RESULTS: OxLDL at entry, but not LDL cholesterol, was associated with the number and size of plaques at follow-up (P = 0.008), also after adjustment for plaque status at entry (P = 0.033). The plasma OxLDL concentration at entry was associated with change in carotid artery IMT (r = 0.17; P = 0.002) and in a stepwise multiple regression analysis this association remained after adjustment for other cardiovascular risk factors (P = 0.005). CONCLUSIONS: These results provide new information, supporting the concept that circulating OxLDL was associated with the silent phase of atherosclerosis progression in clinically healthy men independently of conventional risk factors.

Increased Interleukin-6 levels in pituitary-deficient patients are independently related to their carotid intima-media thickness.

OBJECTIVE: Increased cardiovascular morbidity and mortality has been observed in patients with pituitary deficiency and untreated growth hormone deficiency (GHD). We investigated peripheral inflammatory and fibrinolytic markers and their associations with arterial intima-media thickness (IMT) in GHD. DESIGN: Cross-sectional study. PATIENTS: Thirty-four patients with GHD, but without cardiovascular disease, were compared to healthy controls matched for age, sex, body mass index (BMI) and smoking habits. MEASUREMENTS: IMT of the common carotid artery, C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, plasminogen activator inhibitor-1 (PAI-1) activity and tissue plasminogen activator antigen (tPA-ag) were measured. RESULTS: Median IL-6 concentrations were increased by 208% and 248% in GHD patients compared to BMI-matched and nonobese controls, respectively. Median CRP and tPA-ag levels were increased by 237% and 167% in patients compared to nonobese controls, but not significantly different compared to BMI-matched controls. Plasma levels of fibrinogen and PAI-1 activity did not differ between groups. Age, low-density lipoprotein (LDL) cholesterol, tPA-ag and IL-6 were positively correlated, and IGF-I was negatively correlated to IMT in the patient group, but only age and IL-6 were independently related to IMT. CONCLUSIONS: IL-6 concentrations were increased in GHD patients compared to controls and independently related to IMT in patients. This finding may help to explain the variance in IMT and the increased vascular morbidity and mortality in hypopituitary patients with GHD.

Multiple risk factor intervention reduces cardiovascular risk in hypertensive patients with echolucent plaques in the carotid artery.

OBJECTIVE: In a previously published randomized 6-year study we observed that multiple risk factor intervention reduced cardiovascular risk in high-risk hypertensive men, and that this effect was confined to patients with carotid artery plaques. Hypothetically, the underlying mechanism might have been a stabilization of echolucent, instable, rupture-prone plaques. The aim of the present study was to examine plaque characteristics by B-mode ultrasound in the previous intervention study, and also to investigate the relationship between plaque characteristics at baseline and cardiovascular events during the 6-year follow-up in the two randomization groups. METHODS: High resolution B-mode ultrasound was used to characterize plaque echogenicity in four subgroups - dominantly echolucent, substantially echolucent, dominantly echogenic, and uniformly echogenic. RESULTS: In the usual care group 17 of 32 (53%) patients with echolucent plaques at baseline suffered from a combined end-point (any death or nonfatal myocardial infarction or nonfatal stroke) during follow-up compared with seven of 28 (25%) patients in the intervention group (P = 0.036). The corresponding numbers in patients with echogenic plaques were n = 4/13 (31%) and n = 4/17 (24%), respectively (NS). In the usual care group 11 of 33 (33%) patients with no plaques suffered from a combined end-point during follow-up compared with 11 of 30 (37%) in the intervention group. CONCLUSION: Our data indicate that the beneficial effect of the multiple risk intervention programme was confined to those patients with echolucent plaques. The data have to be confirmed with a large-scale trial.

Endothelium-dependent flow-mediated vasodilatation, insulin resistance and the metabolic syndrome in 60-year-old men.

OBJECTIVES: To evaluate the endothelium-dependent flow-mediated vasodilatation (FMD) in the brachial artery and to study the relationship to insulin sensitivity and to the metabolic syndrome in 60-year-old clinically healthy men. SUBJECTS: The men were randomly selected from the general population (n = 55). The subjects with the metabolic syndrome were defined according to a definition proposed by a working group associated with the World Health Organization (WHO). METHODS: Ultrasound images for measurement of lumen diameter of the brachial artery were recorded before and after reactive hyperaemia induced by occlusion of the artery, both with and without ischaemic hand exercise during the occlusion. Insulin-mediated glucose uptake was determined by euglycaemic hyperinsulinaemic clamp as a measure of insulin sensitivity. RESULTS: The FMD was in the total group 3.2% when hyperaemia was induced by occlusion only and 8.7% after occlusion plus ischaemic hand exercise (P < 0.001, n = 51). However, no relationship was observed between any measure of FMD and insulin-mediated glucose uptake (r = -0.05 and r = 0.06, n = 47, P > 0.30). Furthermore, subjects with the metabolic syndrome (n = 13) did not differ in any measure of FMD compared with those with no risk factors (n = 11). CONCLUSION: In this study the ultrasound method to evaluate endothelial function did not show that low insulin sensitivity or the metabolic syndrome were associated with impaired FMD in otherwise clinically healthy 60-year-old men.

Insulin, insulin propeptides and intima-media thickness in the carotid artery in 58-year-old clinically healthy men. The Atherosclerosis and Insulin Resistance study (AIR).

AIMS: To examine the relationship between specific (intact) insulin, insulin propeptides and subclinical atherosclerosis. METHODS: A cross-sectional study based on a stratified sampling of randomly selected, clinically healthy 58-year-old men (n = 391). Ultrasound examinations of the carotid arteries were performed with measurement of intima-media thickness (IMT) in the common carotid artery and in the carotid artery bulb. Fasting, cross-reacting plasma insulin (RIA), specific (intact) insulin, proinsulin, 32,33 split proinsulin and C-peptide were measured. RESULTS: Plasma concentrations of cross-reacting plasma insulin, specific insulin, proinsulin, 32,33 split proinsulin and C-peptide were univariately associated with common carotid artery IMT. Established risk factors such as blood pressure, smoking, apoB, triglycerides, body mass index (BMI), and waist--hip ratio were also related to IMT. After adjustment for smoking, apoB, blood pressure and triglycerides, cross-reacting plasma insulin, proinsulin and C-peptide but not specific insulin and split 32,33 proinsulin remained associated with carotid artery IMT. No associations remained after adjustment for BMI. CONCLUSIONS: Fasting plasma proinsulin, C-peptide, and insulin by cross-reacting RIA was associated with common carotid artery IMT independent of several conventional risk factors for atherosclerosis. The multicollinearity between the insulin peptides and propeptides makes it difficult to clarify the exact role of each peptide.

Metoprolol controlled release/extended release in patients with severe heart failure: analysis of the experience in the MERIT-HF study.

OBJECTIVES: This study analyzed the effect of the beta(1)-selective beta-blocker metoprolol succinate controlled release/extended release (CR/XL) once daily on mortality, hospitalizations and tolerability in patients with severe heart failure. BACKGROUND: There continues to be resistance to the incorporation of beta-blockers into clinical care, largely due to concerns about their benefit in patients with more severe heart failure. METHOD: SA subgroup of patients from Metoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (MERIT-HF) in New York Heart Association (NYHA) functional class III/IV with left ventricular ejection fraction < 0.25 were identified (n = 795). The analysis was by intention-to-treat. RESULTS: The mean ejection fraction at baseline was 0.19, and the yearly placebo mortality during follow-up was 19.1%. Treatment with metoprolol CR/XL compared to placebo resulted in significant reductions in all predefined mortality end points including: total mortality, 45 versus 72 deaths (risk reduction 39%; 95% confidence interval 11% to 58%; p = 0.0086); sudden death, 22 vs. 39 deaths (45% [7% to 67%]; p = 0.024); and death due to worsening heart failure, 13 vs. 28 deaths (55% [13% to 77%]; p = 0.015). Metoprolol CR/XL also reduced the number of hospitalizations for worsening heart failure by 45% compared with placebo (p < 0.0001). The NYHA functional class improved in the metoprolol CR/XL group compared with placebo (p = 0.0031). Metoprolol CR/XL was well tolerated, with 31% fewer patients withdrawn from study medicine (all causes) compared with placebo (p = 0.027). CONCLUSIONS: This subgroup analysis of the MERIT-HF study shows that patients with severe heart failure receive a similar mortality benefit and a similar reduction in hospitalizations for worsening heart failure with metoprolol CR/XL treatment as those patients included in the total study.

A new method to quantify postexercise ST-deviation--the ST-deficit. A study in men at high and low-risk for coronary heart disease.

BACKGROUND: Quantitative heart rate adjusted exercise ST criteria like microV/beats per minute (bpm) improve the diagnostic accuracy of the exercise ECG. However, there are few quantitative HR adjusted postexercise variables available. The aim of the present exercise study was to evaluate a new such variable from computerized averaging of the postexercise ECG. METHODS: The presence of possible myocardial ischaemia in a population based sample of 74 elderly male hypertensives at high-risk of coronary heart disease, and in 42 age-matched clinically healthy males (reference group) at low-risk was assessed by exercise ECG. All men had a normal resting ECG without signs of ischaemia. VARIABLES STUDIED: standard ST-criteria, ST/HR slope < or =-2.4 microV. bpm-1, shape of the rate-recovery loop, the latter also with a new quantitative variable, the ST-deficit. RESULTS: In spite of a normal resting ECG many subjects showed an abnormal ST/HR slope during exercise, 43% in the hypertension group and 26% in the reference group. An abnormal rate-recovery loop (ST-deficit) also contributed substantially to identify patients with possible myocardial ischaemia, 30 vs. 10%, respectively (P<0.02); cumulatively for the two HR adjusted criteria 53% vs. 29%, respectively (P<0.02). Mean ST-deficit was significantly lower in the high-risk group. CONCLUSIONS: Effort-related myocardial ischaemia is frequently silent in elderly high-risk hypertensives and necessitates testing, preferably with computerized exercise ECG and heart rate adjusted ST criteria. A new quantitative variable to assess the postexercise rate-recovery loop in the time domain, the ST-deficit is described. This variable seems to effectively discriminate between subjects with low and high-risk for coronary heart disease and thus provides new information. Further studies are warranted to validate this variable against myocardial perfusion scintigraphy and coronary angiography.

Effect of metoprolol CR/XL on exercise tolerance in chronic heart failure - a substudy to the MERIT-HF trial.

BACKGROUND: Beta-blockade usually causes a slight reduction in exercise capacity among healthy subjects, while more variable results have been observed in chronic heart failure (CHF), probably related to patients studied, methods and agent used. The effect of metoprolol controlled release/extended release (CR/XL) on peak oxygen uptake (peak VO(2)) in this patient population has not previously been investigated. AIMS: We examined the effect of long-term treatment with the selective beta(1)-receptor blocker metoprolol CR/XL once daily on exercise capacity in patients with CHF. METHODS: Ninety-four patients (70 males and 24 females; mean age 63.6+/-10.6 years) with chronic symptomatic heart failure in New York Heart Association (NYHA) functional class II-IV, and with ejection fraction

Challenges of subgroup analyses in multinational clinical trials: experiences from the MERIT-HF trial.

BACKGROUND: International placebo-controlled survival trials (Metoprolol Controlled-Release Randomised Intervention Trial in Heart Failure [MERIT-HF], Cardiac Insufficiency Bisoprolol Study [CIBIS-II], and Carvedilol Prospective Randomized Cumulative Survival trial [COPERNICUS]) evaluating the effects of b-blockade in patients with heart failure have all demonstrated highly significant positive effects on total mortality as well as total mortality plus all-cause hospitalization. Also, the analysis of the US Carvedilol Program indicated an effect on these end points. Although none of these trials are large enough to provide definitive results in any particular subgroup, it is natural for physicians to examine the consistency of results across various subgroups or risk groups. Our purpose was to examine both predefined and post hoc subgroups in the MERIT-HF trial to provide guidance as to whether any subgroup is at increased risk, despite an overall strongly positive effect, and to discuss the difficulties and limitations in conducting such subgroup analyses. METHODS: The study was conducted at 313 clinical sites in 16 randomization regions across 14 countries, with a total of 3991 patients. Total mortality (first primary end point) and total mortality plus all-cause hospitalization (second primary end point) were analyzed on a time to first event. The first secondary end point was total mortality plus hospitalization for heart failure. RESULTS: Overall, MERIT-HF demonstrated a hazard ratio of 0.66 for total mortality and 0.81 for mortality plus all-cause hospitalization. The hazard ratio of the first secondary end point of mortality plus hospitalization for heart failure was 0.69. The results were remarkably consistent for both primary outcomes and the first secondary outcome across all predefined subgroups as well as for nearly all post hoc subgroups. The results of the post hoc US subgroup showed a mortality hazard ratio of 1.05. However, the US results regarding both the second primary combined outcome of total mortality plus all-cause hospitalization and of the first secondary combined outcome of total mortality plus heart failure hospitalization were in concordance with the overall results of MERIT-HF. Tests of country by treatment interaction (14 countries) revealed a nonsignificant P value of.22 for total mortality. The mortality hazard ratio for US patients in New York Heart Association (NYHA) class III/IV was 0.80, and it was 2.24 for patients in NYHA class II, which is not consistent with causality by biologic gradient. We have not been able to identify any confounding factor in baseline characteristics, baseline treatment, or treatment during follow-up that could account for any treatment by country interaction. Thus we attribute the US subgroup mortality hazard ratio to be due to chance. CONCLUSIONS: Just as we must be extremely cautious in overinterpreting positive effects in subgroups, even those that are predefined, we must also be cautious in focusing on subgroups with an apparent neutral or negative trend. We should examine subgroups to obtain a general sense of consistency, which is clearly the case in MERIT-HF. We should expect some variation of the treatment effect around the overall estimate as we examine a large number of subgroups because of small sample size in subgroups and chance. Thus the best estimate of the treatment effect on total mortality for any subgroup is the estimate of the hazard ratio for the overall trial.

Intact insulin, insulin propeptides, and intima-media thickness in the femoral artery in 58-year-old clinical healthy men--the Atherosclerosis and Insulin Resistance Study.

The aim of this study was to examine the association between intact insulin, insulin propeptides, and femoral artery intima-media thickness. The design was a cross-sectional study and the study group (n = 391) consisted of randomly recruited clinically healthy 58-year-old Swedish men. The intima-media thickness of the common femoral artery was measured with ultrasound. Fasting plasma insulin; intact insulin; proinsulin; 32,33 split-proinsulin; and C-peptide concentrations were assessed. The results showed that the common femoral artery intima-media thickness correlated significantly and univariately with waist-hip ratio, systolic blood pressure, serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, ApoB, low-density lipoprotein peak particle size, and cigarette years. Furthermore, of intact insulin and insulin propeptides, only intact insulin and C-peptide were univariately associated with common femoral artery intima-media thickness (r= 0.14, p < 0.01; r= 0.18, p < 0.01; respectively). In a multiple regression analysis, common femoral artery intima-media thickness was independently associated with systolic blood pressure (beta-coefficient = 0.004, p = 0.002), ApoB (beta-coefficient = 0.338, p < 0.001 ) and cigarette years (beta-coefficient = 0.0004, p < 0.001), (R2= 25%, p

Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: Main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS).

BACKGROUND: Statins reduce cardiovascular events and progression of carotid intima-media thickness (IMT). beta-Blockers are also known to reduce cardiovascular events, but less is known about their effects on carotid IMT. METHODS AND RESULTS: We conducted a randomized, double-blind, placebo-controlled, single-center trial to compare the effects of low-dose metoprolol CR/XL (25 mg once daily) and fluvastatin (40 mg once daily) on the progression of carotid IMT during 36 months of treatment in 793 subjects who had carotid plaque but no symptoms of carotid artery disease. Changes in mean IMT in the common carotid artery and maximal IMT in the bulb were the main outcome variables. Death and cardiovascular events were monitored. Progression of IMT(max) in the carotid bulb at both 18 and 36 months was reduced by metoprolol CR/XL (-0.058 mm/y; 95% CI, -0.094 to -0.023; P=0.004; and -0.023 mm/y; 95% CI, -0.044 to -0.003; P=0.014, respectively). Incidence of cardiovascular events tended to be lower in metoprolol CR/XL-treated patients (5 versus 13 patients, P=0.055). Rate of IMT(mean) progression in the common carotid at 36 months was reduced by fluvastatin (-0.009 mm/y; 95% CI, -0.015 to -0.003; P=0.002). Women in the fluvastatin group had increased frequency of transiently high liver enzymes. CONCLUSIONS: This is the first randomized trial to show that a beta-blocker can reduce the rate of progression of carotid IMT in clinically healthy, symptom-free subjects with carotid plaque. This suggests that beta-blockers may have a favorable effect on atherosclerosis development.